Homosulfanilamide salt of aspergillic acid and method of preparing same



Patented Mar. 20, 1951 HOMOSULFANILAMIDE SALT F ASPER- GILLIC ACID AND METHOD OF PRE- PARING SAME William A. Lott, Maplewood, and Kathryn A. Losee, New Brunswick, N. J., and Max Adler, New York, N. Y., assignors to E. R. Squibb & Sons, New York, N. Y., a corporation of New York N 0 Drawing. Application April 22, 1947,

' Serial No. 743,204

3 Claims. (Cl. 260-250) This invention relates to pharmaceuticals; and it has for its object the provision of advantageous pharmaceuticals essentially comprising combinations of certain chemotherapeutic agents and certain antibiotics, and methods of obtaining such pharmaceuticals.

.The pharmaceuticals of this invention essentially comprise a salt-type combination of a chemotherapeutic basic p-aminomethyl-benzenesulfonamide (especially homosulfanilamide) and an antibiotic capable of forming a salt with an alkali. These salt-type combinations have been found to have both the chemotherapeutic action of th p-aminomethyl-benzene-sulfonamide component and the antibiotic action of the antibiotic component, and, in addition, certain chemical and/or physical properties advantageously utilizable intherapy.

The term a p-aminomethyl-benzene-sulfonamide, as employed herein, means a member of the genus composed of hcmosulfanilamide (also known as a-amino-p-toluene-sulfonamide) and its derivatives. This genus comprises compounds described in U. S. Patent 2,288,531, dated June 30, 1942, including compounds of the formula:

NHQCHZOS O zNHR wherein R is a member of the class consisting of hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxyalkyl, carboxylic acid acyl, and heterocyclic groups. Thus, the genus comprises such compounds as homosulfanilamide; Z-(p-aminomethyl-benzene-sulfonamido) -pyridine; 2- (p-aminomethyl benzene sulfonamido) thiazole; 2-(paminomethyl-benzene-sulfcnamido) -pyrim"dine;

and Z -(p-aminomethyl-benzene-sulfonamido)- 4,6-dimethyl-pyrimidine.

The expression an antibiotic capable of forming a salt with an alkali means a member of the genus composed of acidic antibiotics and amphoteric antibiotics capable of forming a salt with an alkali.

The salt-type combinations of this invention may beobtained by a method essentially comprising interacting, in a solvent for the reactants, a basic p-aminomethyl-benzene-sulfonamide and an antibiotic capable of forming a salt with an alkali; or by a method essentially comprising interacting in an aqueous medium (1) a Watersouble salt obtained by reacting a basic p-aminomethyl-benzene-sulfonamide with an acid and (2) a water-soluble salt obtained by reacting an antibiotic with an alkali (desirably, the cation of the alkali and the anion of the acid being selected from those forming water-insoluble salts with each other).

When prepared in aqueous solution, the solu-. tion of the salt-type combination initially ob 'tained (after separation of any precipitate and suitable adjustment of the concentration) may be therapeutically used as such, inasmuch as any excess or unreacted components of the reaction mixture would not interfere with such use.

either aqueous or non-aqueous solution and containing excess or unreacted components can be therapeutically used without purification.

The thus-obtained homosulfanilamide salt off .acid-penicillin-G, for example, has' both the chemotherapeutic action of homosulfanilarnideand the antibiotic action of penicillin G. The salt is especially suitable for the topical treat-1; ment of infected traumatized areas, being active;

against the following organisms, inter alia:

Gram-positive bacteria, e. g.,

bacteria, e. g., Klebsiella pneumoniae (Friedlander bacillus) and acid-fast bacteria, e. g., Mycobacterium tuberculosis (variety hominis).

The antibiotic employed in the practice of this invention may be either pure or crude and either. naturally (fermentation) derived or synthetic.

Preferably, the crude antibiotic is of such purity.

as to be therapeutically-utilizable per se.

The following examples are illustrative of the invention EXAMPLE 1 Preparation of the homosulfanilamide salt of aspergillic acid 'EXAMPLE 2 Preparation of the homosulfanilamide salt of acid-peniciZZin-G 356.2 mg. (0.001 mol) crystalline sodium-penicillin-G and 222.6 mg. (0.001 mol) homosulfanilamide hydrochloride are dissolved in 0.4 ml. water. Crystallization is then induced (by scratching with a glass rod) and the mass of crystals formed after a short time is triturated with a small A150,; for the same reason, any product recovered from Staphylococcus.- aureus, and CZostridium welchii; Gram-negative amount of water (to remove the sodium chloride formed), collected by filtration, washed with a small amount of water, and dried, in vacuo over phosphorus pentoxide at room temperature. The product, the homosulfanilamide salt or acidpenicillin-G, is highly water-soluble, and melts at 140 C. (with decomposition).

The homosulfanilamide salt of acid-penicillin-G is also obtained on interacting homosulfanilamide and acid-penicillin G in an organic solvent for the reactants, and (in better yield) by interacting in an aqueous medium homosulfanilamide sulfate and barium-penicillin-G.

EXAMPLE 3 Preparation of the homosulfamlamide salt of acid-peniciZlin-F A concentrated aqueous solution of homosulfanilamide sulfate is added to a concentrated aqueous solution of barium-penicillin-F until complete precipitation is obtained. The mixture is then centrifuged and filtered, and the filtrate is freeze-dried, yielding the homosulfanilamide salt of acid-penicilIin-F.

On replacement of the homosulfanilarnide or homosulfani-lamide salt in any of the foregoing examples with any other chemotherapeutic basic p-am inomethyl benzene sulfonamide or salt thereof, the corresponding--antibiotic salt of the replacing p-aminomethyl-benzenesulfonamide is obtained; and on replacement of the antibiotic or salt of the antibiotic employed in any of the fore going examples with any other antibiotic capable of forming a salt with an alkali, or alkali salt of such antibiotic, the 'homosu'lfanilamide salt of the particular antibiotic, is obtained. such other antibiotics (and salts thereof) utilizable in the practice of this invention are acidpenicillin-K and barium-penicillin-X.

The salt-type combinations of this invention are therapeutically utiliza'ble wherever therapy with the p-aminomethy'l-benzene-sulfonamide component thereof is indicated (with the advantage of being more generally effective, because active against a wider variety of organisms); especially, wherever therapy with both the p aminomethylbenzene-sulfonamide component and the antibiotic component is indicated. These salt-type combinations are especiallyadapted for Among dusting (in the powder form obtained on freezedrying) on or into wound (including burns), and may be mixed for this purpose with" the usual inert diluents :or carriers .(impalpable inert powders) e. g., talc, zinc stearate, or corn starch.

The invention may be variously otherwise embodied within the scope of the appended claims.

We claim;

1. The homosulfanilamide salt of aspergillic acid.

2,. The method which comprises interacting, in a solvent for the reactants, homosulfam'lamide and aspergillic acid.

,3. The method which comprises interacting homosulfanilamide and aspergillic acid in substantially dry .alcohol, and removing the alcohol by evaporation under reduced pressure.

WILLIAM A. LOTT. KATHRYN A. LOSEE. MAX ADLER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,324,013 Moore .July 13, 1943 2,352,012 Rosicky A June 20, 1944 2,446,974 Chow Aug. .10, .1948

OTHER REFERENCES Sept. 1945, pp. 244445.

Readers Digest, Nov. 1945, page 39. Lawrence: J. Bact. vol. 49, pp. 149-150 (1945). 

1. THE HOMOSULFANILAMIDE SALT OF ASPERGILLIC ACID. 